Benzamide derivatives for the treatment of diseases mediated by cytokines

ABSTRACT

The invention concerns amide derivatives of Formula (I) wherein: R 1  and R 2  include hydroxy, C 1-6 alkoxy, mercapto, C 1-6 akylthio, amino and heterocyclyl; m and p are independently 0-3; R 3  is halo, cyano or C 1-6 alkoxy; q is 0-4; and R 4  is aryl or cycloalkyl wherein R 4  is optionally substituted with up to 3 substituents having any value defined for each R 1  group; or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.

This application is the national phase of international applicationPCT/GB99/01491 filed May 11, 1999 which designated U.S.

This invention concerns certain amide derivatives which are useful asinhibitors of cytokine mediated disease. The invention also concernsprocesses for the manufacture of the amide derivatives of the invention,pharmaceutical compositions containing them and their use in therapeuticmethods, for example by virtue of inhibition of cytokine mediateddisease.

The amide derivatives disclosed in the present invention are inhibitorsof the production of cytokines such as Tumour Necrosis Factor(hereinafter TNF), for example TNFα, and various members of theinterleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8.Accordingly the compounds of the invention will be useful in thetreatment of diseases or medical conditions in which excessiveproduction of cytokines occurs, for example excessive production of TNFαor IL-1. It is known that cytokines are produced by a wide variety ofcells such as monocytes and macrophages and that they give rise to avariety of physiological effects which are believed to be important indisease or medical conditions such as inflammation and immunoregulation.For example, TNFα and IL-1 have been implicated in the cell signallingcascade which is believed to contribute to the pathology of diseasestates such as inflammatory and allergic diseases and cytokine-inducedtoxicity. It is also known that, in certain cellular systems, TNFαproduction precedes and mediates the production of other cytokines suchas IL-1.

Abnormal levels of cytokines have also been implicated in, for example,the production of physiologically-active eicosanoids such as theprostaglandins and leukotrienes, the stimulation of the release ofproteolytic enzymes such as collagenase, the activation of the immunesystem, for example by stimulation of T-helper cells, the activation ofosteoclast activity leading to the resorption of calcium, thestimulation of the release of proteoglycans from, for example,cartilage, the stimulation of cell proliferation and to angiogenesis.

Cytokines are also believed to be implicated in the production anddevelopment of disease states such as inflammatory and allergicdiseases, for example inflammation of the joints (especially rheumatoidarthritis, osteoarthritis and gout), inflammation of thegastrointestinal tract (especially inflammatory bowel disease,ulcerative colitis, Crohn's disease and gastritis), skin disease(especially psoriasis eczema and dermatitis) and respiratory disease(especially asthma, bronchitis, allergic rhinitis and adult respiratorydistress syndrome), and in the production and development of variouscardiovascular and cerebrovascular disorders such as congestive heartfailure, myocardial infarction. the formation of atheroscleroticplaques, hypertension, platelet aggregation, angina, stroke, reperfusioninjury, vascular injury including restenosis and peripheral vasculardisease, and, for example, various disorders of bone metabolism such asosteoporosis (including senile and postmenopausal osteoporosis). Paget'sdisease, bone metastases, hypercalcaemia, hyperparathyroidism,osteosclerosis, osteoperosis and periodontitis, and the abnormal changesin bone metabolism which may accompany rheumatoid arthritis andosteoarthritis. Excessive cytokine production has also been implicatedin mediating certain complications of bacterial, fungal and/or viralinfections such as endotoxic shock, septic shock and toxic shocksyndrome and in mediating certain complications of CNS surgery or injurysuch as neurotrauma and ischaemic stroke. Excessive cytokine productionhas also been implicated in mediating or exacerbating the development ofdiseases involving cartilage or muscle resorption, pulmonary fibrosis,cirrhosis, renal fibrosis, the cachexia found in certain chronicdiseases such as malignant disease and acquired immune deficiencysyndrome (AIDS), tumour invasiveness and tumour metastasis and multiplesclerosis.

Evidence of the central role played by TNFα in the cell signallingcascade which gives rise to rheumatoid arthritis is provided by theefficacy in clinical studies of antibodies of TNFα (The Lancet, 1994,344, 1125 and British Journal of Rheumatology, 1995, 34, 334).

Thus cytokines such as TNFα and IL-1 are believed to be importantmediators of a considerable range of diseases and medical conditions.Accordingly it is expected that inhibition of the production of and/oreffects of these cytokines will be of benefit in the prophylaxis,control or treatment of such diseases and medical conditions.

Without wishing to imply that the compounds disclosed in the presentinvention possess pharmacological activity only by virtue of an effecton a single biological process, it is believed that the compoundsinhibit the effects of cytokines by virtue of inhibition of the enzymep38 kinase. p38 kinase, otherwise known as cytokine suppressive bindingprotein (hereinafter CSBP) and reactivating kinase (hereinafter RK), isa member of the mitogen-activated protein (hereinafter MAP) kinasefamily of enzymes which is known to be activated by physiological stresssuch as that induced by ionising radiation, cytotoxic agents, andtoxins, for example endotoxins such as bacterial lipopolysaccharide, andby a variety of agents such as the cytokines, for example TNFα and IL-1.It is known that p38 kinase phosphorylates certain intracellularproteins which are involved in the cascade of enzymatic steps whichleads to the biosynthesis and excretion of cytokines such as TNFa andIL-1. Known inhibitors of p38 kinase have been reviewed by G. J. Hansonin Expert Opinions on Therapeutic Patents, 1997, 7, 729-733. p38 kinaseis known to exist in isoforms identified as p38α and p38β.

The compounds disclosed in the present invention are inhibitors of theproduction of cytokines such as TNF, in particular of TNFα, and variousinterleukins, in particular IL-1.

It is known from J. Med. Chem., 1996, 39, 3343-3356, that certainbenzamide derivatives can upregulate the expression of the low densitylipoprotein (LDL) receptor in human hepatocyte cells. The disclosedcompounds included certain N-(2-methoxyphenyl)- andN-(2-halogenophenyl)-benzamide derivatives.

The compound N-(5-benzamido-2-chlorophenyl)benzamide is disclosed in J.Chem. Res. Synop., 1998, 182-183, 886-896 (Chemical Abstracts volume129, abstract 67538).

According to one aspect of the present invention there is provided acompound of the Formula I

wherein:

R¹ and R², which may be the same or different, are selected fromhydroxy, C₁₋₆alkoxy, mercapto, C₁₋₆alkylthio, amino, C₁₋₆alkylamino,di-(C₁₋₆alkyl)amino, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆alkylsulphinyl,C₁₋₆alkylsulphonyl, arylsulphinyl, arylsulphonyl,C₁₋₆alkylaminosulphonyl, di-(C₁₋₆alkyl)aminosulphonyl, nitro, cyano,cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkanoylamino,C₁₋₆alkoxycarbonylamino, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, halo, trifluoromethyl, aryl, arylC₁₋₆alkyl,arylC₁₋₆alkoxy, heteroaryl, heteroarylC₁₋₆alkyl, heterocyclyl andheterocyclyC₁₋₆alkyl;

m and p are independently 0-3, and when m and/or p is 2 or 3 each R¹ orR² group may be the same or different;

R³ is halo, cyano or C₁₋₆alkoxy;

q is 0-4; and

R⁴ is aryl or cycloalkyl wherein R⁴ is optionally substituted with up to3 substituents having any value defined for each R¹ group;

or a pharmaceutically-acceptable salt or in-vivo-cleavable esterthereof;

with the proviso that:

N-[5-(3-cyclohexylpropionylamnino)-2-methoxyphenyl]-4-acetoxybenzamide,

N-[2-bromo-5-(3-cyclohexylpropionylamino)phenyl]-4-hydroxybenzamide,

N-[2-chloro-5-(3-cyclohexylpropionylamino)phenyl]-4-acetoxybenzamide,

N-[2-chloro-5-(3-cyclohexylpropionylamino)phenyl]-4-hydroxybenzamide,

N-[2-fluoro-5-(3-cyclohexylpropionylamino)phenyl]-4-hydroxybenzamide and

N -(5-benzamido-2-chlorophenyl)benzamide

are excluded.

“Aryl” in terms such as “aryl”, “arylC₁₋₆alkyl”, “arylthio”,“arylsulphinyl”, “arylsulphonyl” and “arylC₁₋₆alkoxy” typically meansphenyl or naphthyl, preferably phenyl. “Heteroaryl” in the terms“heteroaryl” and “heteroarylC₁₋₆alkyl” means an aromatic mono- orbicyclic 5-10 membered ring with up to five ring heteroatoms selectedfrom nitrogen, oxygen and sulphur. Examples of ‘heteroaryl’ includethienyl, pyrrolyl, furyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl,quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl and cinnolinyl.“Heterocyclyl” in the terms “heterocyclyl” and “heterocyclylC₁₋₆alkyl”means a non-aromatic mono- or bicyclic 5-10 membered ring with up tofive ring hetero atoms selected from nitrogen, oxygen and sulphur.Examples of ‘heterocyclyl’ include pyrrolinyl, pyrrolidinyl,morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl,dihydropyridinyl and dihydropyrimidinyl. “Cycloalkyl” means anon-aromatic mono- or bicyclic 5-10 membered carbon ring. Examples of“cycloalkyl” include cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.2.1]heptyl and bicyclo[4.4.0]decyl.

Typical values for other generic groups include: for C₁₋₆alkoxy, forexample, methoxy and ethoxy, for C₁₋₆alkylthio, for example, methylthioand ethylthio, for C₁₋₆alkylamino, for example, methylamino andethylamino, for di-(C₁₋₆alkyl)amino, for example, dimethylamino, forC₁₋₆alkoxycarbonyl, for example, methoxycarbonyl and ethoxycarbonyl, forC₁₋₆alkylcarbamoyl, for example, methylcarbamoyl, fordi-C₁₋₆alkylcarbamoyl, for example, dimethylcarbamoyl, forC₁₋₆alkylsulphinyl, for example, methylsulphinyl, forC₁₋₆alkylsulphonyl, for example, methylsulphonyl, forC₁₋₆alkylaminosulphonyl, for example, methylaminosulphonyl, fordi-(C₁₋₆alkyl)aminosulphonyl, for example, dimethylaminosulphonyl, forcyanoC₁₋₆alkyl, for example, cyanomethyl, for hydroxyC₁₋₆alkyl, forexample, hydroxymethyl, for aminoC₁₋₆alkyl, for example, aminomethyl,for C₁₋₆alkanoylamino, for example, formamido and acetamido, forC₁₋₆alkoxycarbonylamino, for example, methoxycarbonylamino, forC₁₋₆alkanoyl, for example, formyl and acetyl, for C₁₋₆alkanoyloxy, forexample, acetoxy, for C₁₋₆alkyl, for example, methyl, ethyl, isopropyland tert-butyl, for C₂₋₆alkenyl, for example, vinyl and allyl, forC₂₋₆alkynyl, for example, ethynyl and 2-propynyl, for halo, for example,fluoro, chloro and bromo, for arylC₁₋₆alkyl, for example, benzyl, andfor arylC₁₋₆alkoxy, for example, benzyloxy.

Any ring in R¹ or R² or any ring in a substituent on R⁴ may beoptionally substituted, for example by up to 3 substituents. Suitablesubstituents include: hydroxy, C₁₋₆alkoxy, mercapto, C₁₋₆alkylthio,amino, C₁₋₆alkylamino, di-(C₁₋₆alkyl)amino, carboxy, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, C₁₋₆alkylsulphinyl,C₁₋₆alkylsulphonyl, arylsulphinyl, arylsulphonyl,C₁₋₆alkylaminosulphonyl, di-(C₁₋₆alkyl)aminosulphonyl, nitro, cyano,cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, amninoC₁₋₆alkyl, C₁₋₆alkanoylamino,C₁₋₆alkoxycarbonylamino, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, halo and trifluoromethyl.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as “isopropyl” are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds ofFormula I defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the property of inhibiting cytokines, in particular TNF. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis from optically active starting materials or by resolution of aracemic form. Similarly, inhibitory properties against TNF may beevaluated using the standard laboratory techniques referred tohereinafter.

Preferably R¹ is hydroxy, C₁₋₆alkoxy, amino, C₁₋₆alkylamino,di-(C₁₋₆alkyl)amino, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,C₁₋₆alkylcarbarnoyl, cyano, C₁₋₆alkanoylamino, C₁₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkyl, halo, trifluoromethyl or heterocyclyl.Further preferably R¹ is aminoC₁₋₆alkyl.

More preferably R¹ is hydroxy, C₁₋₆alkoxy, cyano, halo, morpholino or4-methylpiperazin-1-yl.

Preferably m is 1 or 2.

Conveniently p is 1 and R² is C₁₋₆alkoxy, carboxy, C₁₋₆alkoxycarbonyl,C₁₋₆alkyl or halo.

Preferably p is 0.

Preferably R³ is halo.

Preferably q is 0, 1 or 2. More preferably q is 0.

Preferably R⁴ is phenyl, cyclohexyl or cyclopentyl.

More preferably R⁴ is phenyl.

Preferred substituents on R⁴ are hydroxy, C₁₋₆alkoxy, amino,C₁₋₆alkylamino, di-(C₁₋₆alkyl)amino, carboxy, C₁₋₆alkoxycarbonyl, nitro,cyano, C₁₋₆alkanoylamino, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, C₁₋₆alkyl,halo, trifluoromethyl, phenyl, phenylC₁₋₆alkoxy and heterocyclyl.

More preferably substituents on R⁴ are selected from hydroxy, cyano,dimethylamino, methoxy, ethoxy, fluoro, chloro and morpholino.

Particular novel compounds of the invention include, for example, amidederivatives of the Formula I, or pharnaceutically-acceptable saltsthereof, subject to the exclusions defined hereinbefore, wherein:

(a) R¹ is hydroxy, C₁₋₆alkoxy, amino, C₁₋₆alkylamino,di-(C₁₋₆alkyl)amino, carboxy, C₁₋₆alkoxycarbonyl, nitro, cyano,cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkanoylamino,C₁₋₆alkoxycarbonylamino, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, C₁₋₆alkyl, haloor trifluoromethyl, and m is 1 or 2; and R², R³, R⁴, p and q have any ofthe meanings defined hereinbefore or in this section relating toparticular novel compounds of the invention;

(b) R¹ is a non-aromatic saturated 5- or 6-membered heterocyclic ringwith one or two heteroatoms selected from nitrogen, oxygen and sulphur,and m is 1 or 2; and R², R³, R⁴, p and q have any of the meaningsdefined hereinbefore or in this section relating to particular novelcompounds of the invention;

(c) R¹ is a saturated heterocyclic ring selected from pyrrolidinyl,morpholinyl, piperidinyl, piperazinyl and 4-(C₁₋₆alkyl)piperazinyl, andm is 1 or 2; and R², R³, R⁴, p and q have any of the meanings definedhereinbefore or in this section relating to particular novel compoundsof the invention;

(d) R² is hydroxy, C₁₋₆alkoxy, amino, C₁₋₆alkylamino,di-(C₁₋₆alkyl)amino, carboxy, C₁₋₆alkoxycarbonyl, nitro, cyano,C₁₋₆alkyl, halo or trifluoromethyl, and p is 1; and R¹, R³, R⁴, m and qhave any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention;

(e) p is 0; and R¹, R³, R⁴, m and q have any of the meanings definedhereinbefore or in this section relating to particular novel compoundsof the invention;

(f) R³ is halo; and R¹, R², R⁴, m, p and q have any of the meaningsdefined hereinbefore or in this section relating to particular novelcompounds of the invention;

(g) q is 1, 2, 3 or 4, and R⁴ is cycloalkyl; and R¹, R², R³, m and phave any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention;

(h) q is 0, and R⁴ is phenyl which is optionally substituted with up to3 substituents selected from hydroxy, C₁₋₆alkoxy, amino, C₁₋₆alkylamino,di-(C₁₋₆alkyl)amino, carboxy, C₁₋₆alkoxycarbonyl, nitro, cyano,C₁₋₆alkoxycarbonylamino, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, C₁₋₆alkyl, halo,trifluoromethyl, phenyl, benzyl and benzyloxy; and R¹, R², R³, m and phave any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention;

(i) q is 0, and R⁴ is phenyl which is substituted with 1 or 2substituents selected from heteroaryl, heteroarylC₁₋₆alkyl, heterocyclyland heterocyclylC₁₋₆alkyl; and R¹, R², R³, m and p have any of themeanings defined hereinbefore or in this section relating to particularnovel compounds of the invention;

(j) q is 0, and R⁴ is phenyl which is substituted with 1 or 2heterocyclyl groups comprising a non-aromatic saturated 5- or 6-memberedheterocyclic ring with one or two heteroatoms selected from nitrogen,oxygen and sulphur; and R¹, R², R³, m and p have any of the meaningsdefined hereinbefore or in this section relating to particular novelcompounds of the invention; and

(k) q is 0, and R⁴ is phenyl which is substituted with 1 or 2heterocyclic groups selected from pyrrolidinyl, morpholinyl,piperidinyl, piperazinyl and 4-(C₁₋₆alkyl)piperazinyl; and R¹, R², R³, mand p have any of the meanings defined hereinbefore or in this sectionrelating to particular novel compounds of the invention.

A preferred compound of the invention is an amide derivative of theFormula I wherein R¹ is hydroxy, methoxy, ethoxy, propoxy, isopropoxy,butoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino,carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, cyano,acetamido, acetyl, acetoxy, methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, fluoro, chloro, trifluoromethyl, pyrrolidin-1-yl,morpholino, piperidino, piperazin-1-yl or 4-methylpiperazin-1-yl;

m is 1 or 2;

p is 0;

R³ is fluoro, chloro or bromo;

q is 1, 2 or 3; and

R⁴ is cyclohexyl or cyclopentyl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an amide derivative ofthe Formula I wherein R¹ is hydroxy, methoxy, ethoxy, propoxy,isopropoxy, butoxy, amino, methylamino, ethylamino, dimethylamino,diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, cyano, acetamido, acetyl, acetoxy, methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, trifluoromethyl,pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl or4-methylpiperazin-1-yl;

m is 1 or 2;

p is 0;

R³ is fluoro, chloro or bromo;

q is 0; and

R⁴ is phenyl which is optionally substituted with 1 or 2 substituentsselected from hydroxy, methoxy, ethoxy, propoxy, amino, methylamino,ethylamino, propylamino, dimethylamino, diethylamino, carboxy,methoxycarbonyl, ethoxycarbonyl, nitro, cyano, acetamido, acetyl,acetoxy, methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, phenyl,benzyloxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and4-methylpiperazin-1-yl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an amide derivative ofthe Formula I wherein R¹ is hydroxy, methoxy, ethoxy, cyano, fluoro,chloro, morpholino or 4-methylpiperazin-1-yl;

m is 1 or 2;

p is 0;

R³ is fluoro, chloro or bromo;

q is 0; and

R⁴ is phenyl which is substituted with 1 or 2 substituents selected fromhydroxy, methoxy, dimethylamino, methoxycarbonyl, cyano, fluoro, chloroand morpholino;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an amide derivative ofthe Formula I wherein R¹ is hydroxy, methoxy, ethoxy, amino, cyano,acetoxy, fluoro, chloro, morpholino or 4-methylpiperazin-1-yl;

m is 1 or 2;

p is 0;

R³ is fluoro, chloro or bromo;

q is 0; and

R⁴ is phenyl which is unsubstituted or substituted with 1 or 2substituents selected from hydroxy, methoxy, amino, dimethylamino,methoxycarbonyl, nitro, cyano, fluoro, chloro and morpholino;

or a pharmaceutically-acceptable salt thereof.

Particular preferred compounds of the invention include, for example:

N-[2-chloro-5-(3-cyanobenzamido)phenyl]-3,4-dimethoxybenzamide,

N-[2-chloro-5-(3-dimethylaminobenzamido)phenyl]-3,4-dimethoxybenzamide,

N-[2chloro-5-(4-cyanobenzamido)phenyl]-3,4-dimethoxybenzamide and

N-[2-chloro-5-(4-cyanobenzamido)phenyl]-3-(4-methylpiperazin-1-yl)benzamide;

or the pharmaceutically-acceptable salts thereof.

Further particular preferred compounds of the invention include, forexample:

N-(5-benzamido-2-chlorophenyl)-3,4-dimethoxybenzamide,

N-[2-chloro-5-(3-morpholinobenzamido)phenyl]-3,4-dimethoxybenzamide,

N-[5-(4-acetoxybenzamido)-2-chlorophenyl]-4-cyanobenzamide,

N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide and

N-[2-chloro-5-(3-morpholinobenzamido)phenyl]-4-cyanobenzamide;

or the pharmaceutically-acceptable salts thereof.

A suitable pharmaceutically-acceptable salt of a compound of the FormulaI is, for example, an acid-addition salt of a compound of the Formula Iwhich is sufficiently basic, for example an acid-addition salt with aninorganic or organic acid such as hydrochloric, hydrobromic, sulphuric,trifluoroacetic, citric or maleic acid; or, for example a salt of acompound of the Formula I which is sufficiently acidic, for example analkali or alkaline earth metal salt such as a calcium or magnesium salt,or an ammonium salt, or a salt with an organic base such as methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Various forms of prodrugs are known in the art. For examples of suchprodrug derivatives. see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285(1988); and

e) N. Kakeya, et al., Chem Pharm Bull, 32,692 (1984).

Examples of such pro-drugs may be used to form in-vivo-cleavable estersof a compound of the Formula I. An in-vivo-cleavable ester of a compoundof the Formula I containing a carboxy group is, for example, apharmaceutically-acceptable ester which is cleaved in the human oranimal body to produce the parent acid. Suitablepharmaceutically-acceptable esters for carboxy include C₁₋₆alkoxymethylesters, for example methoxymethyl; C₁₋₆alkanoyloxymethyl esters, forexample pivaloyloxymethyl; phthalidyl esters;C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters, for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, forexample 5-methyl-1,3-dioxolan-2-ylmethyl; and C₁₋₆alkoxycarbonyloxyethylesters, for example 1-methoxycarbonyloxyethyl; and may be formed at anycarboxy group in the compounds of this invention.

In order to use a compound of the Formula I or a pharmaceuticallyacceptable salt or in-vivo-cleavable ester thereof for the therapeutictreatment (including prophylactic treatment) of mammals includinghumans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

According to this aspect of the invention there is provided apharmaceutical composition which comprises an amide derivative of theFormula I, or a pharmaceutically-acceptable salt or in-vivo-cleavableester thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid: binding agents such asstarch; lubricating agents such as magnesium stearate stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calciun carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents. such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia: dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil. suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on Formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the Formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used. Oral administration is howeverpreferred, particularly in tablet form. Typically, unit dosage formswill contain about 1 mg to 500 mg of a compound of this invention.

According to a further aspect of the invention there is provided anamide derivative of the Formula I, or a pharmaceutically-acceptable saltor in-vivo-cleavable ester thereof, as defined hereinbefore for use in amethod of treatment of the human or animal body by therapy.

According to a further aspect of the invention there is provided the useof an amide derivative of the Formula I, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, asdefined hereinbefore or any of those known compounds excluded from thedefinition of the compounds of the invention in the manufacture of amedicament for use in the treatment of diseases or medical conditionsmediated by cytokines.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by cytokines which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in the treatment of diseases or medical conditions mediated by TNF,IL-1, IL-6 or IL-8.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF, IL-1, IL-6 or IL-8 whichcomprises administering to a warm-blooded animal an effective amount ofa compound of the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof in the manufacture of a medicament foruse in the treatment of diseases or medical conditions mediated by TNF.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by TNF which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in inhibiting TNF, IL-1, IL-6 or IL-8.

In a further aspect the present invention provides a method ofinhibiting TNF, IL-1, IL-6 or IL-8 which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula I,or a pharmaceutically-acceptable salt or in-vivo-cleavable esterthereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in inhibiting TNF.

In a further aspect the present invention provides a method ofinhibiting TNF which comprises administering to a warm-blooded animal aneffective amount of a compound of the Formula I, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof in the manufacture of a medicament foruse in the treatment of diseases or medical conditions mediated by p38kinase.

In a further aspect the present invention provides a method of treatingdiseases or medical conditions mediated by p38 kinase which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof. in the manufacture of a medicament foruse in the production of a p38 kinase inhibitory effect.

In a further aspect the present invention provides a method of providinga p38 kinase inhibitory effect which comprises administering to awarm-blooded animal an effective amount of a compound of the Formula I,or a pharmaceutically-acceptable salt or in-vivo-cleavable esterthereof.

In a further aspect the present invention provides the use of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, in the manufacture of a medicament foruse in the treatment of rheumatoid arthritis, asthma, irritable boweldisease, multiple sclerosis, AIDS, septic shock, ischaemic heart diseaseor psoriasis.

In a further aspect the present invention provides a method of treatingrheumatoid arthritis, asthma, irritable bowel disease, multiplesclerosis, AIDS, septic shock, ischaemic heart disease or psoriasiswhich comprises administering to a warm-blooded animal an effectiveamount of a compound of the Formula I, or a pharmaceutically-acceptablesalt or in-vivo-cleavable ester thereof.

The compounds of this invention may be used in combination with otherdrugs and therapies used in the treatment of disease states which wouldbenefit from the inhibition of cytokines, in particular TNF and IL-1.For example, the compounds of the Formula I could be used in combinationwith drugs and therapies used in the treatment of rheumatoid arthritis,asthma, irritable bowel disease, multiple sclerosis, AIDS, septic shock,ischaemic heart disease, psoriasis and the other disease statesmentioned earlier in this specification.

For example, by virtue of their ability to inhibit cytokines, thecompounds of the Formula I are of value in the treatment of certaininflammatory and non-inflammatory diseases which are currently treatedwith a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug(NSAID) such as indomethacin, ketorolac, acetylsalicyclic acid,ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of acompound of the Formula I with a NSAID can result in a reduction of thequantity of the latter agent needed to produce a therapeutic effect.Thereby the likelihood of adverse side-effects from the NSAID such asgastrointestinal effects are reduced. Thus according to a furtherfeature of the invention there is provided a pharmaceutical compositionwhich comprises a compound of the Formula I, or apharnaceutically-acceptable salt or in-vivo-cleavable ester thereof, inconjunction or admixture with a cyclooxygenase inhibitory non-steroidalanti-inflammatory agent, and a pharmaceutically-acceptable diluent orcarrier.

The compounds of the invention may also be used with anti-inflammatoryagents such as an inhibitor of the enzyme 5-lipoxygenase (such as thosedisclosed in European Patent Applications Nos. 0351194, 0375368.0375404, 0375452, 037547, 0381375, 0385662, 0385663, 0385679, 0385680).

The compounds of the Formula I may also be used in the treatment ofconditions such as rheumatoid arthritis in combination withantiarthritic agents such as gold, methotrexate, steroids andpenicillinamine, and in conditions such as osteoarthritis in combinationwith steroids.

The compounds of the present invention may also be administered indegradative diseases, for example osteoarthritis, withchondroprotective, anti-degradative and/or reparative agents such asDiacerhein, hyaluronic acid formulations such as Hyalan. Rumalon,Arteparon and glucosamine salts such as Antril.

The compounds of the Formula I may be be used in the treatment of asthmain combination with antiasthmatic agents such as bronchodilators andleukotriene antagonists.

If formulated as a fixed dose such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically-active agent within its approved dosagerange. Sequential use is contemplated when a combination formulation isinappropriate.

Although the compounds of the Formula I are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit the effects ofcytokines. Thus, they are useful as pharmacological standards for use inthe development of new biological tests and in the search for newpharmacological agents.

An amide derivative of the Formula I, or a pharmaceutically-acceptablesalt or in-vivo-cleavable ester thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Suitable processes are illustrated by, for example, thoseused in J. Med. Chem., 1996, 39, 3343-3356. Such processes, when used toprepare a novel amide derivative of the Formula I are provided as afurther feature of the invention and are illustrated by the followingrepresentative process variants in which, unless otherwise stated, R¹,R², R³, R⁴, m, p and q have any of the meanings defined hereinbefore.Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isdescribed in conjunction with the following representative processvariants and within the accompanying Examples. Alternatively necessarystarting materials are obtainable by analogous procedures to thoseillustrated which are within the ordinary skill of an organic chemist.

a) A compound of the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, may be prepared by reacting an anilineof the Formula II

 with an acid of the Formula III

 or an activated derivative thereof, under standard amide bond formingconditions, wherein variable groups are as hereinbefore defined andwherein any functional group is protected, if necessary, and:

(i) removing any protecting groups;

(ii) optionally forming a pharmaceutically-acceptable salt orin-vivo-cleavable ester.

A suitable activated derivative of an acid of the Formula III is, forexample, an acyl halide, for example an acyl chloride formed by thereaction of the acid and an inorganic acid chloride, for example thionylchloride; a mixed anhydride, for example an anhydride formed by thereaction of the acid and a chloroformate such as isobutyl chloroformate;an active ester. for example an ester formed by the reaction of the acidwith a phenol such as pentafluorophenol, with an ester such aspentafluorophenyl trifluoroacetate or with an alcohol such asN-hydroxybenzotriazole; an acyl azide, for example an azide formed bythe reaction of the acid and an azide such as diphenylphosphoryl azide;an acyl cyanide, for example a cyanide formed by the reaction of an acidand a cyanide such as diethylphosphoryl cyanide; or the product of thereaction of the acid and a carbodiimide such asdicyclohexylcarbodiimide.

The reaction is preferably carried out in the presence of a suitablebase such as, for example an alkali or alkaline earth metal carbonate,alkoxide, hydroxide or hydride, for example sodium carbonate, potassiumcarbonate, sodium ethoxide, potassium butoxide, sodium hydroxide,potassium hydroxide, sodium hydride or potassium hydride, or anorganometallic base such as an alkyl-lithium, for examplen-butyl-lithium, or a dialkylamino-lithium, for example lithiumdi-isopropylamide, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene. Thereaction is also preferably carried out in a suitable inert solvent ordiluent, for example tetrahydrofuran, 1,2-dimethoxyethane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one,dimethylsulphoxide or acetone, and at a temperature in the range, forexample, −78° to 150° C., conveniently at or near ambient temperature.

Typically a carbodiimide coupling reagent is used in the presence of anorganic solvent (preferably an anhydrous polar aprotic organic solvent)at a non-extreme temperature, for example in the region −10 to 40° C.,typically at ambient temperature of about 20° C.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist asappropriate for the protection of the group in question and may beintroduced by conventional methods. Protecting groups may be removed byany convenient method as described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with minimum disturbance of groups elsewhere in themolecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower”, as in, for example, lower alkyl,signifies that the group to which it is applied preferably has 1-4carbon atoms. It will be understood that these examples are notexhaustive. Where specific examples of methods for the removal ofprotecting groups are given below these are similarly not exhaustive.The use of protecting groups and methods of deprotection notspecifically mentioned is of course within the scope of the invention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or arylaliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).

Examples of carboxy protecting groups include straight or branched chainC ₁₋₁₂alkyl groups (for example isopropyl, tert-butyl); lower alkoxylower alkyl groups (for example methoxymethyl, ethoxymethyl,isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (forexample acetoxymethyl, propionyloxymethyl, butyryloxymethyl,pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (forexample 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl loweralkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups(for example trimethylsilyl and tert-butyldimethylsilyl); tri(loweralkyl)silyl lower alkyl groups (for example trimethylsilylethyl), andC₂₋₆alkenyl groups (for example allyl and vinylethyl).

Methods particularly appropriate for the removal of carboxyl protectinggroups include for example acid-, base-, metal- or enzymically-catalysedhydrolysis.

Examples of hydroxy protecting groups include lower alkyl groups (forexample tert-butyl), lower alkenyl groups (for example allyl); loweralkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (forexample tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (forexample allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkylsilyl (for example trimethylsilyl, tert-butyldimethylsilyl) andaryl lower alkyl (for example benzyl) groups.

Examples of amino protecting groups include formyl, aralkyl groups (forexample benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl andfurylmethyl groups; lower alkoxycarbonyl (for exampletert-butoxycarbonyl); lower alkenyloxycarbonyl (for exampleallyloxycarbonyl); aryl lower alkoxycarbonyl groups (for examplebenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl andtert-butyldimethylsilyl); alkylidene (for example methylidene);benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, acid-, base-, metal- or enzymically-catalysedhydrolysis for groups such as p-nitrobenzyloxycarbonyl, hydrogenationfor groups such as benzyl and photolytically for groups such aso-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, byJerry March, published by John Wiley & Sons 1992, for general guidanceon reaction conditions and reagents. The reader is referred toProtective Groups in Organic Synthesis, 2nd Edition, by Green et al.,published by John Wiley & Sons for general guidance on protectinggroups.

The aniline of Formula II may be prepared by reduction of thecorresponding nitro compound of Formula IV.

Typical reaction conditions include the use of ammonium formate in thepresence of a catalyst (for example palladium-on-carbon) in the presenceof an organic solvent (preferably a polar protic solvent), preferablywith heating, for example to about 60° C. Any functional groups areprotected and deprotected as necessary.

The compound of Formula IV may be prepared by reaction of an acid ofFormula V, or an activated derivative thereof,

with an aniline for Formula VI under suitable amide bond formingconditions.

Typical conditions include activating the carboxy group of the compoundof Formula V for example by treatment with a halo reagent (for exampleoxalyl chloride) to form an acyl halide in an organic solvent at ambienttemperature, then reacting the activated compound with the aniline ofFormula VI. Any functional groups are protected and deprotected asnecessary.

(b) A compound of the Formula I, or a pharmaceutically-acceptable saltor in-vivo-cleavable ester thereof, may be prepared by reacting an acidof the Formula V

 or an activated derivative thereof as defined hereinbefore, with ananiline of the Formula VII

 under standard amide bond forming conditions, wherein variable groupsare as hereinbefore defined and wherein any functional group isprotected, if necessary, and:

(i) removing any protecting groups;

(ii) optionally forming a pharmaceutically-acceptable salt orin-vivo-cleavable ester.

The aniline of Formula VII may be prepared by reduction of thecorresponding nitro compound using convention procedures as definedhereinbefore or as illustrated in the Examples.

(c) A compound of the Formula I wherein R¹ or a substituent on R⁴ is anamino group may be prepared by the reduction of a compound of theFormula I wherein R¹ or a substituent on R⁴ is a nitro group.

Typical reaction conditions include the use of ammonium formate orhydrogen gas in the presence of a catalyst, for example a metalliccatalyst such as palladium-on-carbon. Alternatively a dissolving metalreduction may be carried out, for example using iron in the presence ofan acid, for example an inorganic or organic acid such as hydrochloric.hydrobromic, sulphuric or acetic acid. The reaction is convenientlycarried out in the presence of an organic solvent (preferably a polarprotic solvent) and preferably with heating for example to about 60° C.Any functional groups are protected and deprotected as necessary.

The following biological assays and Examples serve to illustrate thepresent invention.

Biological Assays

The following assays can be used to measure the p38 kinase-inhibitory,the TNF-inhibitory and anti-arthritic effects of the compounds of thepresent invention:

In vitro Enzyme Assay

The ability of compounds of the invention to inhibit the enzyme p38kinase was assessed. Activity of particular test compounds against eachof the p38α and p38β isoforms of the enzyme was determined.

Human recombinant MKK6 (GenBank Accesion Number G1209672) was isolatedfrom Image clone 45578 (Genomics, 1996, 33, 151) and utilised to produceprotein in the form of a GST fusion protein in a pGEX vector usinganalogous procedures to those disclosed by J. Han et al., Journal ofBiological Chemistry, 1996, 271, 2886-2891. p38α (GenBank AccessionNumber G529039) and p38β (GenBank Accession Number G1469305) wereisolated by PCR amplification of human lymphoblastoid cDNA (GenBankAccession Number GM1416) and human foetal brain cDNA [synthesised frommRNA (Clontech, catalogue no. 6525-1) using a Gibco superscript cDNAsynthesis kit] respectively using oligonucleotides designed for the 5′and 3′ ends of the human p38α and p38β genes using analogous proceduresto those described by J.Han et al., Biochimica et Biophyhsica Acta,1995, 1265, 224-227 and Y. Jiang et al., Journal of BiologicalChemistry, 1996, 271, 17920-17926.

Both p38 protein isoforms were expressed in e coli in PET vectors. Humanrecombinant p38α and p38β isoforms were produced as 5′ c-myc, 6Histagged proteins. Both MKK6 and the p38 proteins were purified usingstandard protocols: the GST MKK6 was purified using a glutathionesepharose column and the p38 proteins were purified using nickel chelatecolumns.

The p38 enzymes were activated prior to use by incubation with MKK6 for3 hours at 30° C. The unactivated coli-expressed MKK6 retainedsufficient activity to fully activate both isoforms of p38. Theactivation incubate comprised p38α (10 μl of 10 mg/ml) or p38β (10 μl of5 mg/ml) together with MKK6 (10 μl of 1 mg/ml), ‘Kinase buffer’ [100 μl;pH 7.4 buffer comprising Tris (50 mM), EGTA (0.1 mM), sodiumorthovanadate (0.1 mM) and β-mercaptoethanol (0.1%)] and MgATP (30 μl of50 mM Mg(OCOCH₃)₂ and 0.5 mM ATP). This produced enough activated p38enzyme for 3 Microtiter plates.

Test compounds were solubilised in DMSO and 10 μl of a 1:10 dilutedsample in ‘Kinase Buffer’ was added to a well in a Microtiter plate. Forsingle dose testing, the compounds were tested at 10 μM. ‘Kinase AssayMix’ [30 μl; comprising Myelin Basic Protein (Gibco BRL cat. no.1322B-010; 1 ml of a 3.33 mg/ml solution in water), activated p38 enzyme(50 μl) and ‘Kinase Buffer’ (2 ml)) was then added followed by ‘LabelledATP’ [10 μl; comprising 50 μM ATP, 0.1 μCi³³P ATP (AmershamInternational cat. no. BF1000) and 50 mM Mg(OCOCH₃)₂]. The plates wereincubated at room temperature with gentle agitation. Plates containingp38α were incubated for 90 min and plates containing p38β were incubatedfor 45 min. Incubation was stopped by the addition of 50 μl of 20%trichloroacetic acid (TCA). The precipitated protein was phosphorylatedby p38 kinase and test compounds were assessed for their ability toinhibit this phosphorylation. The plates were filtered using a CanberraPackard Unifilter and washed with 2% TCA, dried overnight and counted ona Top Count scintillation counter.

Test compounds were tested initially at a single dose and activecompounds were retested to allow IC₅₀ values to be determined.

In vitro Cell-based Assays

(i) PBMC

The ability of compounds of this invention to inhibit TNFα productionwas assessed by using human peripheral blood mononuclear cells whichsynthesise and secrete TNFα when stimulated with lipopolysaccharide.

Peripheral blood mononuclear cells (PBMC) were isolated from heparinised(10 units/ml heparin) human blood by density centrifugation(Lymphoprep™; Nycomed). Mononuclear cells were resuspended in culturemedium [RPMI 1640 medium (Gibco) supplemented with 50 units/mlpenicillin, 50 μg/ml streptomycin, 2 mM glutamine and 1%heat-inactivated human AB serum (Sigma H-1513)]. Compounds weresolubilised in DMSO at a concentration of 50 mM, diluted 1:100 inculture medium and subsequently serial dilutions were made in culturemedium containing 1% DMSO. PBMCs (2.4×10⁵ cells in 160 μl culturemedium) were incubated with 20 μl of varying concentrations of testcompound (triplicate cultures) or 20 μl culture medium containing 1%DMSO (control wells) for 30 minutes at 37° C. in a humidified (5%CO₂/95% air) incubator (Falcon 3072 ; 96 well flat-bottom tissue cultureplates). 20 μl lipopolysaccharide [LPS E.Coli 0111:B4 (Sigma L-4130),final concentration 10 μg/ml] solubilised in culture medium was added toappropriate wells. 20 μl culture medium was added to “medium alone”control wells. Six “LPS alone” and four “medium alone” controls wereincluded on each 96 well plate. Varying concentrations of a known TNFαinhibitor were included in each test, i.e. an inhibitor of the PDE TypeIV enzyme (for example see Semmler, J. Wachtel. H and Endres, S., Int.J. Immunopharmac. (1993), 15(3), 409-413) or an inhibitor of proTNFαconvertase (for example, see McGeehan, G. M. et al. Nature (1994) 370,558-561). Plates were incubated for 7 hours at 37° C. (humidifiedincubator) after which 100 μl of the supernatant was removed from eachwell and stored at −70° C. (96 well round-bottom plates; Corning 25850).TNFα levels were determined in each sample using a human TNFα ELISA (seeWO92/10190 and Current Protocols in Molecular Biology, vol 2 byFrederick M. Ausbel et al., John Wiley and Sons Inc.).

% inhibition=(LPS alone−medium alone)−(test concentration−mediumalone)×100 (LPS alone−medium alone)

(ii) Human Whole Blood

The ability of the compounds of this invention to inhibit TNFαproduction was also assessed in a human whole blood assay. Human wholeblood secretes TNFα when stimulated with LPS. This property of bloodforms the basis of an assay which is used as a secondary test forcompounds which profile as active in the PBMC test.

Heparinised (10 units/ml) human blood was obtained from volunteers. 160μl whole blood were added to 96 well round-bottom plates (Corning25850). Compounds were solubilised and serially diluted in RPMI 1640medium (Gibco) supplemented with 50 units/ml penicillin. 50 μg/mlstreptomycin and 2 mM glutamine, as detailed above. 20 μl of each testconcentration was added to appropriate wells (triplicate cultures). 20μl of RPMI 1640 medium supplemented with antibiotics and glutamine wasadded to control wells. Plates were incubated for 30 minutes at 37° C.(humidified incubator), prior to addition of 20 μl LPS (finalconcentration 10 μg/ml). RPMI 1640 medium was added to control wells.Six “LPS alone” and four “medium alone” controls were included on eachplate. A known TNFα synthesis/secretion inhibitor was included in eachtest. Plates were incubated for 6 hours at 37° C. (humidifiedincubator). Plates were centrifuged (2000 rpm for 10 minutes) and 100 μlplasma removed and stored at −70° C. (Corning 25850 plates). TNFα levelswere measured by ELISA (see WO92/10190 and Current Protocols inMolecular Biology, vol 2 by Frederick M. Ausbel et al., John Wiley andSons Inc.). The paired antibodies that were used in the ELIZA wereobtained from R&D Systems (catalogue nos. MAB610 anti-human TNFα coatingantibody, BAF210 biotinylated anti-human TNFα detect antibody).

Ex vivo/In vivo Assessment

The ability of the compounds of this invention as ex vivo TNFαinhibitors were assessed in the rat or mouse. Briefly, groups of maleWistar Alderley Park (AP) rats (180-210 g) were dosed with compound (6rats) or drug vehicle (10 rats) by the appropriate route. for exampleperoral (p.o.), intraperitoneal (i.p.) or subcutaneous (s.c.). Ninetyminutes later rats were sacrificed using a rising concentration of CO₂and bled out via the posterior vena cavae into 5 Units of sodiumheparin/ml blood. Blood samples were immediately placed on ice andcentrifuged at 2000 rpm for 10 min at 4° C. and the harvested plasmasfrozen at −20° C. for subsequent assay of their effect on TNFαproduction by LPS-stimulated human blood. The rat plasma samples werethawed and 175 μl of each sample was added to a set format pattern in a96 well round bottom plate (Corning 25850). 50 μl of heparinized humanblood was then added to each well, mixed and the plate was incubated for30 min at 37° C. (humidified incubator). LPS (25 μl; final concentration10 μg/ml) was added to the wells and incubation continued for a further5.5 hours. Control wells were incubated with 25 μl of medium alone.Plates were then centrifuged for 10 min at 2000 rpm and 200 μl of thesupernatants were transferred to a 96 well plate and frozen at −20° C.for subsequent analysis of TNF concentration by ELISA.

Data analysis by dedicated software calculates for each compound/dose:

% inhibition of TNFα=Mean TNFα (Controls)−Mean TNFα (Treated)×100 MeanTNFα (Controls)

Alternatively, mice could be used instead of rats in the aboveprocedure.

Test as Anti-arthritic Agent

Activity of a compound as an anti-arthritic agent was tested as follows.Acid soluble native type II collagen was shown by Trentham et al. [1] tobe arthritogenic in rats; it caused polyarthritis when administered inFreunds incomplete adjuvant. This is now known as collagen-inducedarthritis (CIA) and similar conditions can be induced in mice andprimates. Recent studies have shown that anti-TNF monoclonal antibodies[2] and TNF receptor-IgG fusion proteins [3] ameliorate established CIAindicating that TNF plays a key role in the pathophysiology of CIA.Moreover, the remarkable efficacy reported for anti-TNF monoclonalantibodies in recent rheumatoid arthritis clinical trials indicates thatTNF plays a major role in this chronic inflammatory disease. Thus CIA inDBA/1 mice as described in references 2 and 3 is a tertiary model whichcan be used to demonstrate the anti-arthritic activity of a compound.Also see reference 4.

1. Trentham, D. E. et al., (1977) J. Exp. Med., 146, 857.

2. Williams, R. O. et al., (1992) Proc. Natl. Acad. Sci., 89,9784.

3. Williams. R. O. et al., (1995) Immunology, 84, 433.

4 Badger, M. B. et al., (1996) The Journal of Pharmacology andExperimental Therapeutics, 279, 1453-1461.

Although the pharmacological properties of the compounds of the FormulaI vary with structural change as expected, in general a compound of theFormula I gives over 30% inhibition in the PBMC test at concentrationsup to 50 μM. No physiologically unacceptable toxicity was observed atthe effective dose for compounds tested of the present invention.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) operations were carried out at ambient temperature, i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such as argonunless otherwise stated;

(ii) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany or high pressure liquidchromatography (HPLC) was performed on C18 reverse phase silica, forexample on a Dynamax C-18 60 Å preparative reversed-phase column;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) in general, the end-products of the Formula I have satisfactorymicroanalyses and their structures were confirmed by nuclear magneticresonance (NMR) and/or mass spectral techniques; fast-atom bombardment(FAB) mass spectral data were obtained using a Platform spectrometerand, where appropriate, either positive ion data or negative ion datawere collected; NMR chemical shift values were measured on the deltascale [proton magnetic resonance spectra were determined using a VarianGemini 2000 spectrometer operating at a field strength of 300 MHz or aBruker AM250 spectrometer operating at a field strength of 250 MHz]; thefollowing abbreviations have been used: s, singlet; d, doublet; t,triplet; m, multiplet; br, broad;

(vi) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMRanalysis;

(vii) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus or an oil-bath apparatus; meltingpoints for the end-products of the Formula I were determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

(viii) the following abbreviations have been used:

DMF N,N-dimethylformamide

HPLC high pressure liquid chromatograph

DMSO dimethylsulphoxide

EXAMPLE 1N-[2-chloro-5-(3-dimethylaminobenzamido)phenyl]-3,4-dimethoxybenzamide

Oxalyl chloride (0.11 ml) was added dropwise to a stirred suspension of3-dimethylaminobenzoic acid (0.18 g) in methylene chloride (10 ml) at20° C. DMF (2 drops) was added and the reaction mixture was stirred for4 hours. The solvent was evaporated to give a solid. The solid wasdissolved in methylene chloride (15 ml) and added dropwise over 5minutes to a stirred mixture ofN-(5-amino-2-chlorophenyl)-3,4-dimethoxybenzamide (0.306 g),triethylamine (0.4 ml), 4-dimethylaminopyridine (0.005 g) and methylenechloride (5 ml). The resultant mixture was stirred at 20° C. for 18hours. The reaction mixture was washed with water and with a saturated,aqueous sodium bicarbonate solution, dried (MgSO₄) and evaporated. Theresidual oil was purified by column chromatography on silica gel using a99:1 mixture of methylene chloride and methanol as eluent. There wasthus obtained the title compound (0.109 g), m.p. 98-99° C.;

NMR Spectrum: (CDCl₃) 3.02 (s, 6H), 3.95 (s, 6H), 6.86 (m, 1H), 6.93 (d,1H), 7.1 (d, 1H), 7.31 (t, 1H), 7.42 (m, 2H), 7.54 (d, 1H), 7.98 (m,2H), 8.42 (s, 1H), 8.58 (d, 1H);

Mass Spectrum: M+H⁺ 454.

The N-(5-amino-2-chlorophenyl)-3,4-dimethoxybenzamide used as a startingmaterial was prepared as follows:

3,4-Dimethoxybenzoyl chloride (2 g) was added to a stirred suspension of2-chloro-5-nitroaniline (1.72 g) in pyridine (10 ml) at 20° C. Thereaction mixture was heated to 100° C. for 1 hour. After cooling toambient temperature, the reaction mixture was poured into water (100ml). The resulting precipitate was collected, washed with water anddried. The solid was triturated under methylene chloride (20 ml) to giveN-(2-chloro-5-nitrophenyl)-3,4-dimethoxybenzamide (1.2 g), m.p. 231-232°C.; NMR Spectrum: (DMSOd₆) 3.82 (s, 6H), 7.08 (d, 1H), 7.62 (m, 1H),7.82 (d, 1H), 8.08 (m, 1H), 8.54 (d, 1H), 10.07 (m, 1H);

Mass Spectrum: M+H⁺ 337.

The material so obtained (1.12 g) was added portionwise over 10 minutesto a stirred suspension of iron powder (3.0 g) in a mixture of aceticacid (1 ml), water (10 ml) and ethanol (60 ml) which had been warmed to70-75° C. The resultant mixture was heated to reflux for 1 hour. Themixture was allowed to cool and solid sodium carbonate was added untilthe mixture was basic (pH=8-9). The mixture was filtered and the solidmaterial was washed with methylene chloride. The filtrate was evaporatedand the residue was triturated with ethyl acetate, filtered and thefiltrate was evaporated to give the required starting material as acream-coloured solid, m.p. 146-149° C.; NMR Spectrum: (CDCl₃) 3.70 (s,2H), 3.88 (s, 3H), (s, 3H), 6.31 (m, 1H), 6.74 (d, 1H), 7.06 (d, 1H),7.37 (m, 1H), 7.42 (d, 1H) 7.92 (d, 1H), 8.30 (s, 1H); Mass Spectrum:M+H⁺ 307.

EXAMPLE 2

Using an analogous procedure to that described in Example 1, theappropriate benzoyl chloride was reacted with the appropriate aniline togive the compounds described in Table I.

TABLE I

No. R Note NMR data Mass 1 3-cyano 3.81(s, 6H), 7.06(d, M + H 436 1H),7.50(d, 1H), 7.56(d, 1H), 7.62 (m, 1H), 7.7(m, 1H), 7.75(d, 1H), 8.03(m,2H), 8.15 (d, 1H), 8.4(s, 1H), 9.9(s, 1H), 10.56(s, 1H) 2 4-cyano3.82(s, 6H), 7.07(d, M + H 436 1H), 7.55(d, 1H), 7.58(s, 1H), 7.62(m,1H), 7.7(m, 1H), 8.01(d, 2H), 8.1(d, 3H), 9.9(s, 1H), 10.62(s, 1H) 32-hydroxy 1. 3.82(s, 6H), 6.95(m, M + H 427 2H), 7.05(d, 1H), 7.42 (t,1H), 7.56(m, 4H), 7.95(d, 1H), 8.03(d, 1H), 9.9(s, 1H), 10.49 (s, 1H) 44-methoxy 2. M − H 439 5 2,4-dichloro 2. M + H 479 6 3,4-dichloro 2. M +H 479 7 4-methoxycarbonyl 2. M + H 469 Notes 1. The procedure describedby Brown et al. in J. Med. Chem., 1985, 28, 143-146 was used. 2. Thereaction mixture was purified by HPLC using an increasingly polargradient mixture of from 5 to 30% methanol in methylene chloride.

EXAMPLE 3N-[2-bromo-5-(3-dimethylaminobenzamido)phenyl]-3,4-dimethoxybenzamide

Oxalyl chloride (0.24 ml) was added dropwise to a stirred suspension of3-dimethylaminobenzoic acid (0.36 g) in methylene chloride (15 ml) at20° C. DMF (2 drops) was added and the reaction mixture was stirred for4 hours. The solvent was evaporated to give a yellow solid which wasdissolved in methylene chloride (20 ml) and added dropwise over 5minutes to a stirred mixture ofN-(5-amino-2-bromophenyl)-3,4-dimethoxybenzamide (0.7 g), triethylamine(0.8 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (20ml) which had been cooled to 5-10° C. The reaction mixture was stirredat ambient temperature for 18 hours. The organic phase was washed with asaturated sodium bicarbonate solution, dried (MgSO₄) and evaporated. Theresidual oil was purified by column chromatography on silica gel using a49:1 mixture of methylene chloride and methanol as eluent. The solid soobtained was crystallised from a mixture of ethyl acetate and methyltert-butyl ether to give the title compound (0.564 g), m.p. 184° C.;

NMR Spectrum: (CDCl₃) 3.02 (s, 6H), 3.97 (s, 6H), 6.84 (m, 1H), 6.95 (d,1H), 7.30 (m, 2H), 7.51 (m, 3H), 7.95 (m, 1H), 8.02 (s, 1H), 8.45 (s,1H), 8.56 (d, 1H),

Mass Spectrum: M+H⁺ 498;

Elemental Analysis: Found C, 55.8; H, 4.5; N, 7.9; C₂₄H₂₄N₃BrO₄ H₂Orequires C, 55.8; H, 4.9; N, 8.0%.

The N-(5-amino-2-bromophenyl)-3,4-dimethoxybenzamide used as a startinganiline was prepared as follows:

3,4-Dimethoxybenzoyl chloride (2 g) was added to a stirred solution of2-bromo-5-nitroaniline (2.17 g) at 25° C. The reaction mixture washeated at 100° C. for 5 hours. After cooling, water (25 ml) and 3Mhydrochloric acid (100 ml) were added. The resulting solid was filteredoff and washed with water (50 ml) and dried. The solid was trituratedunder diethyl ether to giveN-(2-bromo-5-nitrophenyl)-3,4-dimethoxybenzamide (2.01 g ) as asandy-coloured solid, m.p. 183-184° C.; NMR Spectrum: (DMSOd₆) 3.92(s,6H), 7.08 (d, 1H), 7.56 (d, 1H), 7.65 (m, 1H), 8.0 (s, 2H), 8.4 (s, 1H),10.09 (s, 1H).

The material so obtained (1.9 g) was added portionwise over 5 minutes toa stirred suspension of iron powder (4.5 g) in a mixture of acetic acid(1.5 ml), water (15 ml) and ethanol (90 ml) which had been warmed to70-75° C. The mixture was heated to reflux for 0.75 hours. Solid sodiumcarbonate was added until the mixture was basic (pH=8-9). The hotmixture was filtered and the residue was washed with hot methanol. Thefiltrates were evaporated and the resultant residue was extracted withhot ethyl acetate (200 ml). The solution was filtered and the filtratewas evaporated to give N-(5-amino-2-bromophenyl)-3,4-dimethoxybenzamide(1.43 g), m.p. 154-155° C.; NMR Spectrum: (CDCl₃) 3.88 (s, 2H), 3.94 (s,3H), 3.96 (s, 3H), 6.38 (m, 1H), 6.93 (d, 1H), 7.25 (d, 1H), 7.46 (m,1H), 7.55 (d, 1H), 8.02 (d, 1H), 8.38 (s, 1H).

EXAMPLE 4N-[2-chloro-5-(3-morpholinobenzamido)phenyl]-3,4-dimethoxybenzamide

3-Morpholinobenzoyl chloride (0.15 g) was added to a stirred solution ofN-(5-amino-2-chlorophenyl)-3,4-dimethoxybenzamide (0.17 g) in pyridine(3 ml). The reaction mixture was stirred and heated to 115° C. for 18hours. The mixture was allowed to cool and poured into water. Themixture was extracted with methylene chloride. The organic extract wasdried (MgSO₄) and evaporated. The resultant solid was azeotroped withtoluene and triturated under diethyl ether to give the title compound(0.1 g), m.p. 147.9-148.3° C.;

NMR Spectrum: (DMSOd₆) 3.19 (s, 4H), 3.78 (s, 4H), 3.85 (s, 6H), 7.07(d, 1H), 7.17 (d, 1H), 7.38 (s, 2H), 7.43 (s, 1H), 7.5 (d, 1H), 7.58 (s,1H), 7.63 (d, 1H), 7.7 (d, 1H), 8.07 (s, 1H), 9.88 (s, 1H), 10.29 (s,1H);

Mass Spectrum: M+H⁺ 496;

Elemental Analysis: Found C, 62.2; H, 5.1; N, 8.2; C₂₆H₂₆N₃₀O₅Cl 0.25H₂Orequires C, 62.4; H, 5.3; N, 8.4%.

The 3-morpholinobenzoyl chloride used as a starting material wasprepared as follows:

A mixture of ethyl 3-bromobenzoate (1.92 ml), morpholine (1.25 ml),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.336 g), sodiumtert-butoxide (1.615 g) and tris(dibenzylideneacetone)dipalladium(0)(0.33 g) and toluene (25 ml) was stirred and heated to 90° C. for 18hours under argon. The reaction mixture was allowed to cool to ambienttemperature and extracted with 1M hydrochloric acid. The aqueous phasewas basified with concentrated sodium hydroxide solution and extractedwith ethyl acetate. The organic phase was dried (MgSO₄) and evaporated.The residual oil was purified by column chromatography on silica gelusing a 47:3 mixtute of methylene chloride and methanol as eluent. Therewas thus obtained N-(3-morpholinobenzoyl)morpholine (0.45 g).

A mixture of the material so obtained, 5M sodium hydroxide solution (2.5ml) and butanol (2 ml) was stirred and heated to 115° C. for 18 hours.The mixture was evaporated and the residue was acidified by the additionof 1M hydrochloric acid solution (12.5 ml). The resultant precipitatewas isolated, washed with water and dried to give 3-morpholinobenzoicacid (0.15 g); NMR Spectrum: (DMSOd₆) 3.1 (t, 4H), 3.73 (t, 4H), 7.19(d, 1H), 7.32 (d, 1H), 7.38 (t, 1H), 7.42(s, 1H).

Oxalyl chloride (0.14 ml) was added to a solution of 3-morpholinobenzoicacid (0.28 g) in methylene chloride (10 ml) which contained DMF (2drops). The reaction mixture was stirred for 18 hours at ambienttemperature. The mixture was evaporated and azeotroped with toluene togive 3-morpholinobenzoyl chloride (0.3 g); Mass Spectrum: M+H⁺ 222.

EXAMPLE 5 N-[2-chloro-5-(4-cyanobenzamido)phenyl]-4-cyanobenzamide

4-Cyanobenzoyl chloride (0.25 g) was added to a stirred mixture ofN-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.39 g), triethylamine(0.51 ml), 4-dimethylaminopyridine (0.01 g) and methylene chloride (25ml). The mixture was stirred at ambient temperature for 18 hours. Themixture was washed with 2M hydrochloric acid solution and with water.The organic phase was dried (MgSO₄)and evaporated. The residue waspurified by column chromatography on silica gel using a 49:1 mixture ofmethylene chloride and methanol as eluent. There was thus obtained thetitle compound (0.1 1 g);

NMR Spectrum: (CDCl₃) 5.5 (s, 2H), 6.58 (d, 1H), 6.7 (d, 1H), 7.18 (d,1H), 7.93 (s, 8H);

Mass Spectrum: M−H⁻399;

Elemental Analysis: Found: C, 65.4; H, 3.7; N, 13.1; C₂₂H₁₃N₄O₂Cl0.25H₂O requires C, 65.2; H, 3.4; N, 13.8%.

The N-(3-amino-4-chlorophenyl)-4-cyanobenzamide used as a startingmaterial was prepared as follows:

4-Cyanobenzoyl chloride (11.92 g) was added slowly to a stirred solutionof 4-chloro-3-nitroaniline (10.4 g) in pyridine (20 ml) and the mixturewas stirred and heated to 115° C. for 18 hours. The mixture was cooledto ambient temperature and poured into water (150 ml) and stirred for 30minutes. The resultant precipitate was isolated, washed with water anddried to give N-[4-chloro-3-nitrophenyl]-4-cyanobenzamide (18 g), m.p.213° C.;

NMR Spectrum: (DMSOd₆) 7.78 (d, 1H), 8.05 (m, 3H), 8.1 (d, 2H), 8.58 (s,1H), 10.93 (s, 1H).

A portion (3.6 g) of the material so obtained was added to a stirredsuspension of iron powder (10 g) in a mixture of ethanol (130 ml), water(30 ml) and glacial acetic acid (4 ml). The mixture was heated to 75° C.for 1 hour and thereafter, whilst hot, basified by the addition ofsodium carbonate. The mixture was filtered and the filtrate wasevaporated. The resultant solid was stirred in water for 3 hours. Thesolid was isolated and dried to give the required starting material (2.7g), m.p. 237.7° C.; NMR Spectrum: (DMSOd₆) 5.44 (s, 2H), 6.98 (m, 1H),7.21 (d, 1H), 7.42 (d, 1H), 8.07 (d, 2H), 8.14 (d, 2H), 10.36 (s, 1H).

EXAMPLE 6

Using an analogous procedure to that described in Example 5, theappropriate benzoyl chloride was reacted with the appropriate aniline togive the compounds described in Table 11.

TABLE II

No. (R¹)_(m) Note NMR data Mass 1 3,4,5-trimethoxy 3.78(s, 3H), 3.88(s,M − H 6H), 7.37(s, 2H), 464 7.58(d, 1H), 7.72(d, 1H), 8.02(d, 2H),8.05(s, 1H), 8.10(d, 2H), 10.02(s, 1H), 10.64(s, 1H) 2 3,4-diethoxy 1.1.38(t, 6H), 4.09(m, M − H 4H), 9.83(s, 1H), 462 10.62(s, 1H) 32-hydroxy 6.65(t, 1H), 6.9(d, M + H 1H), 7.23(m, 1H), 392 7.42(d, 1H),7.62 (m, 1H), 7.93(m, 1H), 7.99(d, 2H), 8.12(d, 2H), 8.98(d, 1H),10.64(s, 1H) 4 2-hydroxy-4-methoxy 3.75(s, 3H), 6.52(s, M + H 1H),6.61(m, 1H), 422 7.50(d, 1H), 7.68 (m, 1H), 7.99(m, 3H), 8.1(d, 2H),8.88(s, 1H), 10.64 (s, 1H), 10.68(s, 1H), 12.2(s, 1H) 54-(4-methylpiperazin-1-yl) 2.8(s, 3H), 3.4(m, M + H 4H), 4.0(m, 2H), 4747.08(d, 2H), 7.52(d, 1H), 7.72(d, 1H), 7.91(d, 2H), 8.0(d, 2H), 8.12(m,3H), 9.8(s, 1H), 10.68(s, 1H) 6 3-(4-methylpiperazin-1-yl) 3.19(s, 3H),3.5(d, M + H 2H), 3.92(d, 2H), 474 7.22(d, 1H), 7.41(t, 1H), 7.5(d, 1H),7.58(t, 1H), 7.72(m, 1H), 8.02(d, 2H), 8.1(m, 2H), 10.06(s, 1H),10.73(s, 1H) 7 4-morpholino 0.84(m, 2H), 1.29 M + H (m, 2H), 3.23(m, 4612H), 3.75(m, 2H), 6.86(m, 1H), 7.01 (d, 1H), 7.13(d, 1H), 7.38(d, 1H),7.5(d, 1H), 7.7(t, 1H), 7.9(d, 1H), 7.99(d, 2H), 8.05 (d, 2H), 9.68(s,1H), 10.62(s, 1H) Notes 1. The standard procedure was adapted to thefollowing: Phosphoryl chloride (0.03 ml) was added dropwise to a stirredmixture of N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.08 g),3,4-diethoxybenzoic acid (0.062 g) and pyridine (4 ml) which had beencooled to −15° C. The mixture was stirred at −15° C. for 3 hours. Themixture was allowed to warm to ambient temperature and was stirred for16 hours. The mixture was diluted with water and stirred overnight. Theresultant precipitate was isolated, # washed with diethyl ether anddried under vacuum at 55° C. to give the tabulated compound (0.026 g).

EXAMPLE 7N-[2-chloro-5-(4-cyanobenzamido)phenyl]-3-fluoro-4-(4-methylpiperazin-1-yl)benzamide

Phosphoryl chloride (0.1 I ml) was added dropwise to a stirred mixtureof N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.2 g),3-fluoro-4-(4-methylpiperazin-1-yl)benzoic acid (0.26 g) and pyridine (2ml) which had been cooled to −10° C. The reaction mixture was allowed towarm to ambient temperature and was stirred for 16 hours. The mixturewas diluted with water and was stirred overnight. The precipitate wasisolated, washed with diethyl ether and dried under vacuum at 55° C.There was thus obtained the title compound as a solid (0.212 g);

Mass Spectrum: (M−H)⁻ 490.

The 3-fluoro-4-(4-methylpiperazin-1-yl)benzoic acid used as a startingmaterial was obtained as follows:

A mixture of 3,4-difluorobenzonitrile (8.65 g), N-methylpiperazine (7.2ml), triethylamine (9.1 ml) and acetonitrile (12 ml) was stirred andheated to reflux for 2 hours. The mixture was evaporated and the residuewas purified by column chromatography using a 1:5:94 mixture oftriethylamine, methanol and methylene chloride as eluent. There was thusobtained 3-fluoro-4-(4-methylpiperazin-1-yl)benzonitrile as an oil whichslowly crystallised to give a white solid (12.47 g), m.p. 60-63° C.; NMRSpectrum: (CDCl₃) 2.37 (s, 3H), 2.61 (t, 4H), 3.24 (t, 4H), 6.89 (m,1H), 7.27 (m, 1H), 7.35 (m, 1H).

A portion (3 g) of the material so obtained was dissolved in 6Nhydrochloric acid (30 ml) and the solution was heated to reflux for 13hours. The mixture was cooled to ambient temperature. The precipitatewas isolated, washed with water and air-dried to give the requiredstarting material (1.63 g). Elemental analysis showed the crystals tocontain approximately 6 equivalents of water. NMR Spectrum: (DMSOd₆)2.81 (s, 3H), 3.28 (m, 8H), 7.17 (m, 1H), 7.62 (m, 1H), 7.71 (m, 1H),10.9 (s, 1H).

The N-(3-amino-4-chlorophenyl)4-cyanobenzamide used as a startingmaterial was synthesised as follows:

Triethylamine (6.7 ml) was added to a stirred mixture of3-amino4-chloroaniline (3.44 g), 4-cyanobenzoyl chloride (4.0 g) andmethylene chloride (50 ml) which had been cooled to 0° C. The reactionmixture was allowed to warm to ambient temperature and was stirred for 5hours. The mixture was concentrated to approximately one third of theoriginal volume and a saturated aqueous sodium bicarbonate solution wasadded. The resultant solid was isolated, washed with water and withmethanol and dried under vacuum at 55° C. to give the required startingmaterial (5.23 g); NMR Spectrum: (DMSOd₆) 5.37 (s, 2H), 6.9 (m, 1H),7.14 (d, 1H), 7.35 (d, 1H), 7.98 (d. 2H), 8.08 (d, 2H), 10.28 (s, 1H).

EXAMPLE 8N-[5-(3-dimethylaminobenzamido)-2-fluorophenyl]-3,4-dimethoxybenzamide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g) inmethylene chloride (5 ml) was added to a stirred mixture of3,4-dimethoxybenzoic acid (0.91 g),N-(3-amino-4-fluorophenyl)-3-dimethylaminobenzamide (0.14 g), DMF (2 ml)and 4-dimethylaminopyridine (0.004 g). The reaction mixture was stirredat ambient temperature for 18 hours. Water (20 ml) and methylenechloride (10 ml) were added. The organic phase was washed with asaturated aqueous sodium bicarbonate solution, dried (MgSO₄) andevaporated. The residual oil was purified by column chromatography onsilica gel using a 49:1 mixture of methylene chloride and methanol aseluent. The material so obtained was triturated under diethyl ether.There was thus obtained the title compound (0.084 g) as a colourlessolid, m.p. 187-188° C.; NMR Spectrum: (CDCl₃) 3.02 (s, 6H), 3.97 (s,6H), 6.86 (m, 1H), 6.93 (d, 1H), 7.09 (d, 1H), 7.16 (t, 1H), 7.25 (m,1H), 7.32 (t, 1H), 7.41 (m, 1 H), 7.5 (d, 1H), 7.88 (m, 1H), 7.97 (s,1H), 8.04 (s, 1H), 8.42 (m, 1H);

Mass Spectrum: M+H⁺ 438;

Elemental Analysis: Found C, 65.4; H, 5.5; N, 9.5; C₂₄H₂₄NFO₄ requiresC, 65.8; H, 5.4; N, 9.6%.

The N-(3-amino4-fluorophenyl)-3-dimethylaminobenzamide used as astarting material was prepared as follows:

Oxalyl chloride (1.2 ml) was added dropwise over 5 minutes to a stirredsuspension of 3-dimethylaminobenzoic acid (1.81 g) in methylene chloride(20 ml) at 20° C. DMF (2 drops) was added and the reaction mixturestirred for 4 hours at ambient temperature. The solvent was evaporatedand the residue was dissolved in methylene chloride (25 ml) and addedover 5 minutes to a stirred mixture of 4-fluoro-3-nitroaniline (1.56 g),triethylamine (4.1 ml) and methylene chloride (25 ml). The solution wasstirred for 18 hours. The organic layer was washed with 3M hydrochloricacid and with water, dried (MgSO₄) and evaporated. The residual solidwas triturated under methyl tert-butyl ether and then under methylenechloride. There was thus obtainedN-(4-fluoro-3-nitrophenyl)-3-dimethylaminobenzamide (0.96 g), m.p.176-177° C.; NMR Spectrum: (DMSOd₆) 2.93 (s, 6H), 6.92 (m, 1H), 7.2 (m2H), 7.31 (t, 1H), 7.56 (q, 1H), 8.11 (m, 1H), 8.63 (m, 1H), 10.58 (s,1H).

10% Palladium-on-carbon (0.09 g) was added to a stirred suspension ofthe nitro compound so obtained (0.910 g) in ethanol (90 ml) The mixturewas hydrogenated at atmospheric pressure and ambient temperature untilhydrogen uptake ceased. The catalyst was removed by filtration and thefiltrate was evaporated. The solid residue was purified by columnchromatography on silica gel using a 49:1 mixture of methylene chlorideand methanol as eluent. There was thus obtained the required startingmaterial (0.74 g);

NMR Spectrum: (CDCl₃) 3.0 (s, 6H), 3.78 (s, 2H), 6.7 (m, 1H), 6.92 (m,2H), 7.05 (d, 1H), 7.30 (m, 2H), 7.37 (m, 1H), 7.68 (s, 1H).

EXAMPLE 9 N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide

Iron powder (2.79 g) was added to a stirred suspension ofN-(5-benzamido-2-chlorophenyl)-4-methoxy-2-nitrobenzamide (2.13 g) in amixture of ethanol (100 ml), water (20 ml) and acetic acid (4 ml). Themixture was stirred and heated to reflux for 6 hours. The mixture wascooled to ambient temperature. Water (50 ml) was added and the resultantmixture was basified by the addition of sodium carbonate. The mixturewas filtered and the filtrate was evaporated. The residue was trituratedunder water. The resultant solid was isolated and dried under vacuum at40° C. There was thus obtained the title compound (0.911 g);

NMR Spectrum: (DMSOd₆) 3.72 (s, 3H), 6.09 (d, 1H), 6.27 (s, 1H), 6.62(s, 2H), 7.45-7.61 (m, 4H), 7.66-7.72 (m, 2H), 7.95 (d, 2H), 8.07 (s,1H), 9.52 (s, 1H), 10.37 (s, 1H);

Mass Spectrum: M+H⁺ 396 and 398.

The N-(5-benzamido-2-chlorophenyl)-4-methoxy-2-nitrobenzamide used as astarting material was prepared as follows:

Benzoyl chloride (5.2 ml) was added to a stirred mixture of2,4-diaminochlorobenzene (6.42 g), triethylamine (12.5 ml) and methylenechloride (100 ml) which had been cooled to 0° C. The mixture was allowedto warm to ambient temperature and was stirred for 16 hours. The mixturewas evaporated and the residue was triturated under a saturated aqueoussodium bicarbonate solution. The resultant solid was isolated, washed inturn with water and isohexane and dried under vacuum at 55° C. There wasthus obtained N-(3-amino-4-chlorophenyl)benzamide as a solid (10.38 g);NMR Spectrum: (DMSOd₆) 5.32 (s, 2H), 6.9 (m, 1H), 7.1 (d, 1H), 7.37 (d,1H), 7.52 (m, 3H), 7.9 (d, 2H), 10.05 (s, 1H).

Oxalyl chloride (0.781 ml) was added dropwise to a stirred mixture of4-methoxy-2-nitrobenzoic acid (1.6 g), DMF (a few drops) and methylenechloride (30 ml) which had been cooled to 0° C. The mixture was allowedto warm to ambient temperature and was stirred for 4 hours. The mixturewas evaporated. The residue was dissolved in methylene chloride (10 ml)and added dropwise to a stirred mixture ofN-(3-amino-4-chlorophenyl)benzamide (2.0 g), triethylamine (2.49 ml) andmethylene chloride (30 ml). The resultant mixture was stirred at ambienttemperature for 16 hours. The precipitate was isolated, washed with 1Naqueous hydrochloric acid solution and with methanol and dried undervacuum at 40° C. There was thus obtained the required starting material(2.49 g); NMR Spectrum: (DMSOd₆) 3.9 (s, 3H), 7.39 (d, 1H), 7.47-7.62(m, 5H), 7.72 (d, 1H), 7.78 (d, 1H), 7.97 (d, 2H), 8.14 (s, 1H), 10.28(s, 1H), 10.46 (s, 1H);. Mass Spectrum: M+H⁺ 426 and 428.

EXAMPLE 10 N-(5-benzamido-2-chlorophenyl)-3,4dimethoxybenzamide

Phosphoryl chloride (0.074 g) was added to a stirred mixture of3,4-dimethoxybenzoic acid (0.088 g), N-(3-amino-4-chlorophenyl)benzamide(0.1 g) and pyridine (1 ml) which had been cooled to 0° C. The mixturewas allowed to warm to ambient temperature and was stirred for 16 hours.The mixture was poured into 1N aqueous hydrochloric acid solution andthe resultant solid was isolated, washed with a saturated aqueous sodiumbicarbonate solution and dried under vacuum at 55° C. There was thusobtained the title compound (0.088 g);

NMR Spectrum: (DMSOd₆) 3.83 (m, 6H), 7.09 (d, 1H), 7.55 (m, 6H), 7.72(d, 1H), 7.95 (d, 2H), 8.08 (s, 1H), 9.88 (s, 1H), 10.4 (s, 1H);

Mass Spectrum: M−H⁻409.

EXAMPLE 11N-[2-chloro-5-(2-nitrobenzamido)phenyl]-3,4-dimethoxybenzamide

3,4-Dimethoxybenzoyl chloride (1.55 g) was added to a stirred mixture ofN-(3-amino-4-chlorophenyl)-2-nitrobenzamide (1.5 g) and pyridine (20 ml)and the mixture was stirred and heated to 80° C. for 16 hours. Themixture was cooled to ambient temperature and evaporated. The residuewas partitioned between methylene chloride and 1N aqueous hydrochloricacid solution. The organic phase was washed with a saturated aqueoussodium bicarbonate solution and evaporated. The residue was trituratedunder ethyl acetate. The resultant solid was isolated, washed with asaturated aqueous sodium bicarbonate solution and dried under vacuum at40° C. There was thus obtained the title compound (1.63 g);

NMR Spectrum: (DMSOd₆) 7.08 (d, 1H), 7.52-7.57 (m, 3H), 7.62 (d, 1H),7.74-7.8 (m, 2H), 7.86 (t, 1H), 7.87 (s, 1H), 8.13 (d, 1H);

Mass Spectrum: M+H⁺ 456 and 458.

The N-(3-amino-4-chlorophenyl)-2-nitrobenzamide used as a startingmaterial was prepared as follows:

2-Nitrobenzoyl chloride (4.64 ml) was added to a stirred mixture of3-amino-4-chloroaniline (5 g), triethylamine (9.78 ml) and methylenechloride (300 ml) and the reaction mixture was stirred at ambienttemperature for 16 hours. The mixture was partitioned between methylenechloride and a saturated aqueous sodium bicarbonate solution. Theorganic phase was evaporated and the residue was purified by columnchromatography on silica to give the required starting material (3.02g); NMR Spectrum: (DMSOd₆) 5.38 (s, 2H), 6.74 (d, 1H), 7.11 (d, 1H),7.27 (s, 1H), 7.7-7.75 (m, 2H), 7.84 (t, 1H), 8.1 (d, 1H), 10.5 (s, 1H);Mass Spectrum: M+H⁺ 292 and 294.

EXAMPLE 12N-15-(2-aminobenzamido)-2-chlorophenyl]-3,4-dimethoxybenzamide

Using an analogous procedure to that described in Example 9,N-[2-chloro-5-(2-nitrobenzamido)phenyl]-3,4-dimethoxybenzamide wasreduced by iron powder in the presence of acetic acid to give the titlecompound in 43% yield;

NMR Spectrum: (DMSOd₆) 3.82 (s, 6H), 6.32 (s, 2H), 6.58 (t, 1H), 7.74(d, 1H), 7.08 (d, 1H), 7.19 (t, 1H), 7.47 (d, 1H), 7.52-7.64 (m, 4H),8.04 (s, 1H), 9.88 (s, 1H), 10.13 (s, 1H);

Mass Spectrum: M+H⁺ 426.

EXAMPLE 13N-[2-chloro-5-(3-dimethylaminobenzamido)4-fluorophenyl]-3,4-dimethoxybenzamide

A mixture of 3,4-dimethoxybenzoyl chloride (0.5 g),N-(5-amino-4-chloro-2-fluorophenyl)-3-dimethylaminobenzamide (0.781 g)and pyridine (8 ml) was stirred at ambient temperature for 18 hours. Themixture was evaporated and the residue was partitioned between methylenechloride and a saturated aqueous copper sulphate solution. The organicphase was washed in turn with water and a saturated aqueous sodiumchloride solution, dried (MgSO₄) and evaporated. The residue waspurified by column chromatography on silica using a 99:1 mixture ofmethylene chloride and methanol as eluent. There was thus obtained thetitle compound as a solid (0.328 g);

NMR Spectrurn: (CDCl₃) 3.02 (s, 6H), 3.98 (s, 6H), 6.96 (m, 2H), 7.06(m, 1H), 7.06-7.47 (m, 3H), 7.47 (m, 1H), 7.6 (m, 1H), 8.01 (s, 1H), 8.2(s, 1H), 9.53 (m, 1H);

Mass Spectrum: M+H⁺ 472 and 474.

The N-(5-amino4-chloro-2-fluorophenyl)-3-dimethylaminobenzamide used asa starting material was prepared as follows:

Phthalic anhydride (11.83 g) was added to a solution of2-chloro4-fluoroaniline (11.08 g) in glacial acetic acid (150 ml) andthe mixture was stirred and heated to 100° C. for 2 hours. The mixturewas allowed to cool to ambient temperature and the precipitate wasisolated, washed with water and dried under vacuum. There was thusobtained N-(2-chloro-4-fluorophenyl)phthalimide which was used withoutfurther purification.

A mixture of nitric acid (4.6 ml) and sulphuric acid (5 ml) was addedgradually to a stirred mixture of theN-(2-chloro-4-fluorophenyl)phthalimide so obtained and sulphuric acid(30 ml) which was cooled in an ice-water bath, the rate of addition wassuch that the internal reaction temperature did not exceed 30° C. Theresulting clear solution was stirred at ambient temperature for 1 hour.A mixture (250 ml) of ice and water was added and the precipitated solidwas isolated and dried under vacuum. There was thus obtainedN-(2-chloro-4-fluoro-5-nitrophenyl)phthalimide as a solid (17.9 g); NMRSpectrum: (CDCl₃): 7.58 (d, 1H), 7.88 (m, 2H), 8.01 (m, 2H), 8.16 (d,1H); Mass Spectrum: M−H⁻ 319 and 321.

A mixture of ethanol (450 ml), water (65 ml) and acetic acid (6.5 ml)was stirred and heated to 50° C. Iron powder (9 g) was added followed byportionwise addition over 10 minutes ofN-(2-chloro-4-fluoro-5-nitrophenyl)phthalimide (8.98 g). The resultantmixture was stirred and heated to reflux for 2 hours. The mixture wascooled to ambient temperature and basified by the addition of solidsodium carbonate. The mixture was filtered and the filtrate wasevaporated. The residue was partitioned between methylene chloride and asaturated aqueous sodium bicarbonate solution. The organic extract waswashed with a saturated aqueous sodium chloride solution, dried oversodium sulphate and evaporated. There was thus obtainedN-(5-amino-2-chloro-4-fluorophenyl)phthalimide as a solid (6.3 g);

NMR Spectrum: (CDCl₃) 3.87 (s, 2H), 6.74 (d. 1H), 7.2 (d. 1H), 7.81 (m,2H), 7.96 (m, 2H);

Mass Spectrum: M−H⁻ 289 and 291.

Pyridine (2.0 ml) was added to a mixture ofN-(5-amino-2-chloro-4-fluorophenyl)phthalimide (2.9 g),3-dimethylaminobenzoyl chloride hydrochloride (3.06 g) and methylenechloride (20 ml) and the mixture was stirred at ambient temperature for18 hours. The reaction mixture was diluted with methylene chloride (200ml) and washed in turn with a saturated aqueous copper sulphate solutionand water. The organic solution was dried (MgSO₄) and evaporated. Theresidue was triturated under ethyl acetate. The solid so obtained wasisolated and washed with ethyl acetate and with diethyl ether. There wasthus obtainedN-(4-chloro-2-fluoro-5-phthalimidophenyl)-3-dimethylaminobenzamide as asolid (2.46 g); NMR Spectrum: (DMSOd₆) 2.94 (s, 6H), 6.94 (m, 1H), 7.28(m, 3H), 7.8-7.92 (m, 2H), 7.94 (m, 2H), 8.02 (m, 2H); Mass Spectrum:M+H⁺ 438 and 440.

A mixture of the material so obtained, ethanolamine (0.68 ml) andmethylene chloride (40 ml) was stirred at ambient temperature for 4hours. The mixture was diluted with methylene chloride (200 ml) and theresultant solution was washed with water and with a saturated aqueoussodium chloride solution, dried over sodium sulphate and evaporated.There was thus obtainedN-(5-amino-4-chloro-2-fluorophenyl)-3-dimethylaminobenzamide as a solid(1.26 g); NMR Spectrum: (CDCl₃) 3.02 (s, 6H), 3.94 (s, 2H), 4.0 (broads, 2H), 6.88 (m, 1H), 7.04 (m, 1H), 7.07 (s, 1H), 7.25 (m, 1H), 7.32 (t,1H), 7.98 (broad s, 1H), 8.08 (d, 1H); Mass Spectrum: M+H⁺ 308 and 310.

EXAMPLE 14 N-[5-(4-acetoxybenzamido)-2-chlorophenyl]-4-cyanobenzamide

Oxalyl chloride (0.35 ml) was added to a stirred suspension of4-acetoxybenzoic acid (0.57 g) in methylene chloride (15 ml) which hadbeen cooled to 0° C. DMF (2 drops) was added and the mixture was stirredat ambient temperature for 4 hours. The mixture was evaporated to give4-acetoxybenzoyl chloride which was used without further purification. Amixture of the acid chloride so obtained,N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.813 g) and pyridine (15ml) was stirred and heated at 100° C. for 16 hours. The mixture wascooled to ambient temperature and poured into 2N aqueous hydrochloricacid solution (175 ml). The precipitate was isolated, washed with waterand dried. The material so obtained was purified by columnchromatography on silica using a 7:3 mixture of isohexane and ethylacetate as eluent. There was thus obtained the title compound (0.74 g);m.p. 195-196° C.

NMR Spectumn: (DMSOd₆) 2.3 (s, 3H), 7.28 (d, 2H), 7.51 (d, 1H), 7.73 (m,1H), 7.81 (m, 4H), 8.12 (m, 3H), 10.08 (s, 1H), 10.64 (s, 1H);

Mass Spectrum: M+H⁺ 434.

EXAMPLE 15 N-[2-chloro-5-(3-morpholinobenzamido)phenyl]-4-cyanobenzamide

Using an analogous procedure to that described in Example 14,3-morpholinobenzoyl chloride was reacted withN-(3-amino-4-chlorophenyl)-4-cyanobenzamide to give the title compoundin 42% yield;

NMR Spectrum: (DMSOd₆) 3.13 (t, 4H), 3.73 (t, 4H), 7.17 (s, 1H), 7.43(m, 1H), 7.6 (d, 1H), 7.8 (m, 1H), 8.06 (m, 3H), 8.1 (m, 3H), 8.17 (m,1H);

Mass Spectrum: M+H⁺ 461.

EXAMPLE 16

Pharmaceutical Compositions

The following illustrate representative pharmaceutical dosage forms ofthe invention as defined herein (the active ingredient being termed“Compound X”), for therapeutic or prophylactic use in humans:

mg/tablet (a) Tablet I Compound X 100 Lactose Ph. Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% W/V paste) 2.25Magnesium stearate 3.0 mg/tablet (b) Tablet II Compound X 50 Lactose Ph.Eur 223.75 Croscamellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone (5% W/V paste) 2.25 Magnesium stearate 3.0mg/tablet (c) Tablet III Compound X 1.0 Lactose Ph. Eur 93.25Croscarmellose sodium 4.0 Maize starch paste (5% W/V paste) 0.75Magnesium stearate 1.0 mg/capsule (d) Capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium 1.5 (50 ml/mg) (e) Injection 1 Compound X 5.0% w/v1M Sodium hydroxide solution 15.0% v/v 0.1M Hydrochloric acid (to adjustpH to 7.6) Polyetbylene glycol 400 4.5% w/v Water for injection to 100%(10 mg/ml) (f) Injection II Compound X 1.0% w/v Sodium phosphate BP 3.6%w/v 0.1M Sodium hydroxide solution 15.0% v/v Water for injection to 100%(1 mg/ml, buffered to pH 6) (g) Injection III Compound X 0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 4003.5% w/v Water for injection to 100% mg/ml (h) Aerosol I Compound X 10.0Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0Dichlorodifluoromethane 490.0 mg/ml (i) Aerosol II Compound X 0.2Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0Dichiorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 mg/ml (j)Aerosol III Compound X 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 mg/ml (k) Aerosol IV Compound X 2.5 Soyalecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6 ml (l) Ointment Compound X 40 mg Ethanol300 μl Water 300 μl 1-Dodecylazacycloheptan-2-one 50 μl Propylene glycolto 1 ml Note The above fonnulations may be obtained by conventionalprocedures well known in the pharmaceutical art. The tablets (a)-(c) maybe enteric coated by conventional means, for example to provide acoating of cellulose acetate phthalate. The aerosol formulations (h)-(k)may be used in conjunction with standard, metered dose aerosoldispensers, and the suspending agents sorbitan trioleate and soyalecithin may be replaced by an alternative suspending agent such assorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerololeate or oleic acid.

What is claimed is:
 1. A compound of the Formula I

wherein: R¹ is selected from hydroxy, C₁₋₆alkoxy, mercapto,C₁₋₆alkylthio, amino, C₁₋₆alkylamino, di-(C₁₋₆alkyl)amino, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, C₁₋₆alkylcarbamoyl,di-C₁₋₆alkylcarbamoyl, C₁₋₆alkylsulphinyl, C₁₋₆alkylsulphonyl,arylsulphinyl, arylsulphonyl, C₁₋₆alkylaminosulphonyl,di-(C₁₋₆alkyl)aminosulphonyl, nitro, cyano, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, C₁₋₆alkanoylamino,C₁₋₆alkoxycarbonylamino, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, halo, trifluoromethyl, aryl, arylC₁₋₆alkyl,arylC₁₋₆alkoxy, heteroaryl, heteroarylC₁₋₆alkyl, heterocyclyl orheterocyclylC₁₋₆alkyl; m is 1 or 2 and when m is 2 each R¹ group may bethe same or different; R³ is halo; q is 0-4; and R⁴ is aryl orcycloalkyl wherein R⁴ is optionally substituted with up to 3substituents having any value defined for each R¹ group; or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof;with the proviso that:N-[2-bromo-5-(3-cyclohexylpropionylamino)phenyl]-4-hydroxybenzamide,N-[2-chloro-5-(3 -cyclohexylpropionylamino)phenyl]-4-acetoxybenzamide,N-[2-chloro-5-(3-cyclohexylpropionylamino)phenyl]-4-hydroxybenzamide andN-[2-fluoro-5-(3-cyclohexylpropionylamino)phenyl]-4-hydroxybenzamide areexcluded.
 2. A compound of the Formula I according to claim 1, whereinR¹ is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, amino,methylamino, ethylamino, dimethylamino, diethylamino, carboxy,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, cyano, acetamido,acetyl, acetoxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,fluoro, chloro, trifluoromethyl, pyrrolidin-1-yl, morpholino,piperidino, piperazin-1-yl or 4-methylpiperazin-1-yl; R³ is fluoro,chloro or bromo; q is 1, 2 or 3; and R⁴ is cyclohexyl or cyclopentyl; ora pharmaceutically-acceptable salt thereof.
 3. A compound of the FormulaI according to claim 1, wherein R¹ is hydroxy, methoxy, ethoxy, propoxy,isopropoxy, butoxy, amino, methylamino, ethylamino, dimethylamino,diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, cyano, acetamido, acetyl, acetoxy, methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, trifluoromethyl,pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl or4-methylpiperazin-1-yl; R³ is fluoro, chloro or bromo; q is 0; and R⁴ isphenyl which is optionally substituted with 1 or 2 substituents selectedfrom hydroxy, methoxy, ethoxy, propoxy, amino, methylamino, ethylamino,propylamino, dimethylamino, diethylamino, carboxy, methoxycarbonyl,ethoxycarbonyl, nitro, cyano, acetamido, acetyl, acetoxy, methyl, ethyl,fluoro, chloro, bromo, trifluoromethyl, phenyl, benzyloxy,pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl or4-methylpiperazin-1-yl; or a pharmaceutically-acceptable salt thereof.4. A compound of the Formula I according to claim 1, wherein R¹ ishydroxy, methoxy, ethoxy, cyano, fluoro, chloro, morpholino or4-methylpiperazin-1-yl; R³ is fluoro, chloro or bromo; q is 0; and R⁴ isphenyl which is substituted with 1 or 2 substituents selected fromhydroxy, methoxy, dimethylamino, methoxycarbonyl, cyano, fluoro, chloroand morpholino; or a pharmaceutically-acceptable salt thereof.
 5. Acompound of the Formula I according to claim 1, wherein R¹ is hydroxy,methoxy, ethoxy, amino, cyano, acetoxy, fluoro, chloro, morpholino or4-methylpiperazin-1-yl; R³ is fluoro, chloro or bromo; q is 0; and R⁴ isphenyl which is unsubstituted or substituted with 1 or 2 substituentsselected from hydroxy, methoxy, amino, dimethylamino, methoxycarbonyl,nitro, cyano, fluoro, chloro and morpholino; or apharmaceutically-acceptable salt thereof.
 6. A compound of the Formula Iaccording to claim 1, selected from:N-[2-chloro-5-(3-cyanobenzamido)phenyl]-3,4-dimethoxybenzamide,N-[2-chloro-5-(3-dimethylaminobenzamido)phenyl]-3,4-dimethoxybenzamide,N-[2-chloro-5-(4-cyanobenzamido)phenyl]-3,4-dimethoxybenzamide andN-[2-chloro-5-(4-cyanobenzamido)phenyl]-3-(4-methylpiperazin-1-yl)benzamide;or pharmaceutically-acceptable salts thereof.
 7. A compound of theFormula I according to claim 1, selected from:N-(5-benzamido-2-chlorophenyl)-3,4-dimethoxybenzamide,N-[2-chloro-5-(3-morpholinobenzamido)phenyl]-3,4-dimethoxybenzamide,N-[5-(4-acetoxybenzamido)-2-chlorophenyl]-4-cyanobenzamide,N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide andN-[2-chloro-5-(3-morpholinobenzamido)phenyl]-4-cyanobenzamide; orpharmaceutically-acceptable salts thereof.
 8. A process for thepreparation of a compound of the Formula I, or apharmaceutically-acceptable salt or in-vivo-cleavable ester thereof,according to claim 1 which comprises: (a) reacting of a compound of theFormula II

 with an acid of the Formula III

 or an activated derivative thereof, under standard amide bond formingconditions, wherein variable groups are as defined in claim 1 andwherein any functional group is protected if necessary, and: (i)removing any protecting groups; (ii) optionally forming apharmaceutically-acceptable salt or in-vivo-cleavable ester; (b)reacting of an acid of the Formula V

 or an activated derivative thereof, with an aniline of the Formula VII

 under standard amide bond forming conditions, wherein variable groupsare as defined in claim 1 and wherein any functional group is protected,if necessary, and: (i) removing any protecting groups; (ii) optionallyforming a pharmaceutically-acceptable salt or in-vivo-cleavable ester;or (c) for the preparation of a compound of the Formula I according toclaim 1 wherein R¹ a substituent on R⁴ is an amino group, reducing of acompound of the Formula I wherein R¹ or a substituent on R⁴ is a nitrogroup.
 9. A pharmaceutical composition which comprises a compound of theFormula I, or a pharmaceutically-acceptable salt or in-vivo-cleavableester thereof, according to claim 1 in association with apharmaceutically-acceptable diluent or carrier.
 10. A method of treatinga disease or medical condition mediated by cytokines which comprisesadministering to a warm-blooded animal an effective amount of a compoundof the Formula I, or a pharmaceutically-acceptable salt orin-vivo-cleavable ester thereof, according to claim 1.